title: FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice.
abstract: Prion diseases are fatal neurodegenerative disorders and no effective treatment has been established to date. In this study, we evaluated the effect of FK506 (tacrolimus), a macrolide that is known to be a mild immunosuppressant, on prion infection, using cell culture and animal models. We found that FK506 markedly reduced the abnormal form of prion protein (PRNP(Sc)) in the cell cultures (N2a58 and MG20) infected with Fukuoka-1 prion. The levels of autophagy-related molecules such as LC3-II, ATG12-ATG5 and ATG7 were significantly increased in the FK506-treated cells, and resulted in the increased formation of autolysosomes. Upregulation of the autophagy-related molecules was also seen in the brains of FK506-treated mice and the accumulation of PRNP(Sc) was delayed. The survival periods in mice inoculated with Fukuoka-1 were significantly increased when FK506 was administered from day 20 post-inoculation. These findings provide evidence that FK506 could constitute a novel antiprion drug, capable of enhancing the degradation of PRNP(Sc) in addition to attenuation of microgliosis and neuroprotection.
authors.affiliation: Department of Molecular Microbiology and Immunology; Nagasaki University Graduate School of Biomedical Sciences; Sakamoto, Nagasaki Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakagaki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Satoh
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishibashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fuse
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.forename: Yuji O
authors.initials: YO
authors.lastname: Kamatari
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
authors.forename: Kazuto
authors.initials: K
authors.lastname: Shigematsu
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Iwamaru
authors.forename: Takato
authors.initials: T
authors.lastname: Takenouchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitani
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D016559:Tacrolimus
keywords: FK506; autophagy; degradation; microglia; prion; tacrolimus; therapy